Purpose:

Calculate and plot mutational signatures for all samples using COSMIC signatures and Alexandrov et al, 2013 mutational signatures.

Usage

To run this from the command line, use: Rscript -e "rmarkdown::render('analyses/mutational-signatures/01-known_signatures.Rmd', clean = TRUE)"

This assumes you are in the top directory of the repository.

Setup

Packages and functions

Import necessary functions.

# Magrittr pipe
`%>%` <- dplyr::`%>%`

# Import specialized functions
source(file.path("util", "mut_sig_functions.R"))

# Load this library
library(deconstructSigs)
library(tidyverse)
── Attaching core tidyverse packages ────────────────────────────────────────────────────────────────────────────────────────────── tidyverse 2.0.0 ──
✔ dplyr     1.1.1     ✔ readr     2.1.4
✔ forcats   1.0.0     ✔ stringr   1.5.0
✔ ggplot2   3.4.2     ✔ tibble    3.2.1
✔ lubridate 1.9.2     ✔ tidyr     1.3.0
✔ purrr     1.0.1     
── Conflicts ──────────────────────────────────────────────────────────────────────────────────────────────────────────────── tidyverse_conflicts() ──
✖ dplyr::filter() masks stats::filter()
✖ dplyr::lag()    masks stats::lag()
ℹ Use the conflicted package (<http://conflicted.r-lib.org/>) to force all conflicts to become errors

Set up directory paths.

data_dir <- file.path("..", "..", "data")
input_dir <- "input"
results_dir <- "results"
plots_dir <- "plots"
figures_dir <- file.path("..", "..", "figures")

cosmicv2_plots <- file.path(plots_dir, "cosmicv2")
nature_plots <- file.path(plots_dir, "nature")
cosmicv3_plots <- file.path(plots_dir, "cosmicv3")

scratch_dir <- file.path("..", "..", "scratch", "mutational-signatures")
cosmicv2_scratch <- file.path(scratch_dir, "cosmicv2")
cosmicv3_scratch <- file.path(scratch_dir, "cosmicv3")
nature_scratch <- file.path(scratch_dir, "nature")

Make new directories for the results.

if (!dir.exists(results_dir)) {
  dir.create(results_dir)
}
if (!dir.exists(cosmicv2_plots)) {
  dir.create(cosmicv2_plots, recursive = TRUE)
}
if (!dir.exists(nature_plots)) {
  dir.create(nature_plots, recursive = TRUE)
}
if (!dir.exists(cosmicv3_plots)) {
  dir.create(cosmicv3_plots, recursive = TRUE)
}

if (!dir.exists(scratch_dir)) {
  dir.create(scratch_dir)
}
if (!dir.exists(cosmicv2_scratch)) {
  dir.create(cosmicv2_scratch)
}
if (!dir.exists(cosmicv3_scratch)) {
  dir.create(cosmicv3_scratch)
}
if (!dir.exists(nature_scratch)) {
  dir.create(nature_scratch)
}

Read in data

# Declare file path for consensus file
consensus_file <- file.path(data_dir, "snv-consensus-plus-hotspots.maf.tsv.gz")

Read in the consensus MAF file.

# Read in the file
maf <- data.table::fread(consensus_file, data.table = FALSE)

Read in color palettes

Read in the histology colors and labels.

histology_label_mapping <- readr::read_tsv(
  file.path(figures_dir, "palettes", "histology_label_color_table.tsv")
) %>% 
  # Select just the columns we will need for plotting
  dplyr::select(Kids_First_Biospecimen_ID, display_group, display_order, hex_codes) %>% 
  # Reorder display_group based on display_order
  dplyr::mutate(display_group = forcats::fct_reorder(display_group, display_order))
Rows: 2841 Columns: 11
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr (9): Kids_First_Biospecimen_ID, sample_type, integrated_diagnosis, Notes...
dbl (2): n, display_order

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.

Set up gradient color palette for the bubble matrix plots.

gradient_col_palette <- readr::read_tsv(
  file.path(figures_dir, "palettes", "gradient_color_palette.tsv")
)
Rows: 11 Columns: 2
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr (2): color_names, hex_codes

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.
# Won't need NA color this time. 
gradient_col_palette <- gradient_col_palette %>%
  dplyr::filter(color_names != "na_color")

Read in the metadata and set it up with the color palette. Separate BS_ids into intial CNS tumors and other tumors, as mutational signatures analyses will be run on a different set of signatures for each group.

metadata_df <- readr::read_tsv(file.path(data_dir, "histologies.tsv"), guess_max = 10000) %>% 
#  dplyr::select("Kids_First_Biospecimen_ID", "experimental_strategy") %>%
  dplyr::inner_join(histology_label_mapping, by = "Kids_First_Biospecimen_ID") %>% 
  dplyr::rename(Tumor_Sample_Barcode = "Kids_First_Biospecimen_ID") 
Warning: One or more parsing issues, call `problems()` on your data frame for details, e.g.:
  dat <- vroom(...)
  problems(dat)
Rows: 43729 Columns: 55
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr (38): Kids_First_Biospecimen_ID, sample_id, aliquot_id, Kids_First_Parti...
dbl (17): age_at_diagnosis_days, OS_days, EFS_days, age_last_update_days, no...

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.
initial_pretx_tumors <- metadata_df %>%
  filter(tumor_descriptor == "Initial CNS Tumor" & age_at_diagnosis_days < age_at_chemo_start) %>%
  pull(Tumor_Sample_Barcode)
  

# pretx_tumors <- readr::read_tsv(file.path(input_dir, "CBTN_all_therapy_20220922.tsv")) %>%
#   mutate(Pretreatment = case_when(`Age at Diagnosis` < `Age at Chemotherapy Start` ~ "yes",
#                                   `Age at Diagnosis` > `Age at Chemotherapy Start` ~ "no",
#                                   TRUE ~ as.character(NA))) %>%
#   filter(Pretreatment == "yes") %>%
#   pull(cohort_participant_id)
# 
# initial_pretx_tumors <- metadata_df %>%
#   filter(tumor_descriptor == "Initial CNS Tumor" & cohort_participant_id %in% pretx_tumors) %>%
#   pull(Tumor_Sample_Barcode)

Read in tmb-all file with WGS and WXS region lengths so they can be used for the Mb denominator.

# Set up BED region file for TMB calculations
region_sizes <- readr::read_tsv(file.path(data_dir, "snv-mutation-tmb-all.tsv")) %>%
  dplyr::select(Tumor_Sample_Barcode, region_size)
Rows: 2766 Columns: 5
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr (2): Tumor_Sample_Barcode, experimental_strategy
dbl (3): mutation_count, region_size, tmb

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.

Set up data

Determine how many mutations we have per sample.

mut_per_sample <- maf %>%
  dplyr::group_by(Tumor_Sample_Barcode) %>%
  dplyr::tally() %>%
  dplyr::arrange(n)

summary(mut_per_sample$n)
     Min.   1st Qu.    Median      Mean   3rd Qu.      Max. 
      1.0     125.2     989.0    3567.7    2101.8 1077834.0 

Graph this.

ggplot2::ggplot(mut_per_sample, ggplot2::aes(x = n, geom = "density")) +
  ggplot2::geom_density() +
  ggplot2::theme_classic()

Make mutation data into deconstructSigs input format.

# Convert to deconstructSigs input
sigs_input <- mut.to.sigs.input(
  mut.ref = maf,
  sample.id = "Tumor_Sample_Barcode",
  chr = "Chromosome",
  pos = "Start_Position",
  ref = "Reference_Allele",
  alt = "Allele",
  bsg = BSgenome.Hsapiens.UCSC.hg38::BSgenome.Hsapiens.UCSC.hg38
)
Warning in mut.to.sigs.input(mut.ref = maf, sample.id = "Tumor_Sample_Barcode", : Some samples have fewer than 50 mutations:
  BS_02QV7ZWP, BS_1B00Q25Y, BS_3DV5FVPQ, BS_4SCDT7M9, BS_7KR13R3P, BS_91HP99HY, BS_BTDQZ60Q, BS_GQFPB8F3, BS_KHJMCFQR, BS_KT3GAAQV, BS_P7VR731D, BS_QF7M4SHH, BS_ST7KGV85, BS_W60PB1DS, BS_X0KN4VVW, BS_YGDHJ68W, BS_Z8GRJ71M, BS_GJ2KS7BT, BS_08QFCDXB, BS_0W0G7PYS, BS_026TDAF1, BS_09983DA9, BS_1V616KKY, BS_1XT92Z85, BS_1ZX8B4H6, BS_2HE0SGCP, BS_33FDZ9QY, BS_2WEA24FV, BS_2W1D018F, BS_3CW6E0W8, BS_37P1RE8J, BS_3FMM6P58, BS_3KHY7S7N, BS_39JWYN4D, BS_41Q1D6PV, BS_443KSJR9, BS_473TYSNE, BS_4882NV0Q, BS_4A55PHAE, BS_4CDQ0JJ1, BS_4CGJYHHN, BS_4EY5V954, BS_557R1AGJ, BS_6CKTRR1X, BS_75BBX7JP, BS_6TR1TNS7, BS_790WPA1C, BS_85EWSYGV, BS_7PF27EEG, BS_88GET7GV, BS_8QR5CHV7, BS_9EFHG5PZ, BS_981ME2R1, BS_9N1V6VN2, BS_9PEXXJMK, BS_9X5AABEM, BS_A6E869SH, BS_ADMV7AV5, BS_A0R18CS1, BS_AM3NM05Y, BS_AT709G19, BS_AYDXB2NA, BS_AVXJSWEN, BS_AZ7C646B, BS_B05V3JN7, BS_B64J2XCQ, BS_BAD2CHGE, BS_BJ6GHH0W, BS_BQK1JF37, BS_BYXPP48M, BS_CVCR0QTK, BS_D0QNVE94, BS_DJ05Y3P6, BS_DSAGRKDR, BS_DVPGAFPS, BS_E6RGTGE7, BS_E9CF9YSP, BS_E6V9F7GA, BS_EBPF8GTD, BS_ENJZQ5F6, BS_FFZGMSMQ, BS_ENP5SS80, BS_FWVSVP0T, BS_G6W2T7CV, BS_GQN8GB9K, BS_GZJADN7T, BS_H7AWWS55, BS_GVZPVW85, BS_HWT4F4Z1, BS_HRAPJC76, BS_J8CDEQ26, BS_K59BPPX3, BS_KQM96PHV, BS_KF7X1WDR, BS_KY0N6ZCY, BS_N9KWJSW0, BS_MCB9QYD6, BS_M3KA4SSE, BS_N9MHYWDZ, BS_NBW2EEMA, BS_NVB25WVY, BS_NZX1S9QT, BS_P65W011T, BS_PHVX4NQ6, BS_PPC82HCS, BS_Q2R56X78, BS_Q9MMJ9H4, BS_QF0WQY17, BS_QRTBPSN6, BS_QV60J6XZ, BS_RPRNKMCQ, BS_RK6YX3RE, BS_RRN8YDWK, BS_RRFV4R8C, BS_SDKP0388, BS_SEFYKVEW, BS_SQ2FFGA1, BS_SYQ1GRJA, BS_T1NQGNEX, BS_TSCE1B96, BS_TW4ZGQ3E, BS_T2ASQ6ZF, BS_TE7Q5QWK, BS_V1BNA817, BS_V54KSGNF, BS_VEK54PE0, BS_VGTP4Z43, BS_VGXWS93R, BS_WV0GH7EN, BS_XA22ZVF2, BS_W3AK2Q14, BS_XE7YZD41, BS_YP0K170J, BS_YRVPJSEG, BS_YZ22MXW3, BS_Z0C4H94E, BS_Z8X2WQFH, TARGET-10-PATZFF-09A-01D, TARGET-50-PALJIP-01A-01D, TARGET-10-PASJMK-09A-01D, TARGET-10-PARHES-09A-01D, TARGET-10-PATWXC-09A-01D, TARGET-10-PATDMN-09A-01D, TARGET-10-PASSPP-09A-01D, TARGET-10-PARWID-09A-01D, TARGET-10-PASXLT-09A-01D, TARGET-10-PARASZ-09A-01D, TARGET-10-PANYZE-09A-01D, TARGET-10-PASZJW-03A-01D, TARGET-10-PAPZNK-03A-01D, TARGET-10-PATSDS-03A-01D, TARGET-10-PATGWP-09A-01D, TARGET-10-PATCZN-09A-01D, TARGET-10-PARJXW-09A-01D, TARGET-10-PARXLS-09A-01D, TARGET-10-PAUBXP-09A-01D, TARGET-10-PATZYC-09A-01D, TARGET-50-PAKFYV-01A-01D, TARGET-10-PASHXL-09A-01D, TARGET-10-PASXUU-09A-01D, TARGET-50-PAJPCM-01A-01D, TARGET-50-PAJNRH-01A-01D, TARGET-10-PASHNK-09A-01D, TARGET-10-PATLPN-03A-01D, TARGET-10-PARMIH-09A-01D, TARGET-50-PAKXWB-01A-01D, TARGET-50-PAJNNC-01A-01D, TARGET-10-PATYWV-09A-01D, TARGET-10-PARYGI-03A-01D, TARGET-10-PASKTG-09A-01D, TARGET-40-PASKZZ-01A-01D, TARGET-10-PATSLH-09A-01D, TARGET-10-PAPDUV-09A-01D, TARGET-10-PARNXJ-09A-01D, TARGET-10-PARPYJ-09A-01D, TARGET-10-PARGFL-09A-01D, TARGET-10-PAUBLL-09A-01D, TARGET-50-PAJMEP-01A-01D, TARGET-40-PASYUK-01A-01D, TARGET-50-PAKPDF-01A-01D, TARGET-10-PASILW-09A-01D, TARGET-10-PASIIY-09A-01D, TARGET-10-PAPHED-09A-01D, TARGET-30-PATNPW-01A-01D, TARGET-30-PASKRS-01A-01D, TARGET-30-PATSKE-01A-01D, TARGET-30-PAUTVX-01A-01D, TARGET-30-PAMMXF-01A-01W, TARGET-30-PATSJV-01A-01D, TARGET-10-PARBCW-09A-01D, TARGET-30-PATBJI-01A-01D, TARGET-10-PARBGG-09A-01D, TARGET-30-PAURZH-01A-01D, TARGET-30-PAUZTF-01A-01D, TARGET-30-PASDDP-01A-01D, TARGET-10-PANXEE-09A-01D, TARGET-30-PAUPDY-01A-01D, TARGET-30-PATUNX-01A-01D, TARGET-30-PAUGIP-01A-01D, TARGET-10-PANXCX-09A-01D, TARGET-30-PATYDC-01A-01D, TARGET-30-PAUJTY-01A-01D, TARGET-30-PAUKRF-01A-01D, TARGET-30-PATRXC-01A-01D, TARGET-40-PALKGN-01A-01D, TARGET-30-PAUIWS-01A-01D, TARGET-10-PANVAW-09A-01D, TARGET-30-PASGNT-01A-01D, TARGET-30-PAPBJT-01A-01W, TARGET-30-PATRHD-01A-01D, TARGET-30-PASRWE-01A-01D, TARGET-30-PATYMK-01A-01D, TARGET-30-PAUUZU-01A-01D, TARGET-30-PARVWL-01A-01D, TARGET-30-PATAAV-01A-01D, TARGET-30-PASRSG-01A-01D, TARGET-30-PARTCE-01A-01D, TARGET-10-PANZZI-09A-01D, TARGET-30-PAVALS-01A-01D, TARGET-30-PAUXUP-01A-01D, TARGET-30-PAUMXC-01A-01D, TARGET-10-PARJMY-09A-01D, TARGET-30-PAUBPW-09A-01D, TARGET-10-PAPHRV-09A-01D, TARGET-30-PASUYL-01A-01D, TARGET-30-PASAFG-01A-01D, TARGET-30-PATUPR-09A-01D, TARGET-10-PARGGI-09A-01D, TARGET-10-PAPBCK-09A-01D, TARGET-30-PATHJU-09A-01D, TARGET-30-PAVEZM-01A-01D, TARGET-30-PATFTR-01A-01D, TARGET-30-PASMUB-01A-01D, TARGET-30-PASLRM-01A-01D, TARGET-30-PASZST-01A-01D, TARGET-30-PAUELT-01A-01D, TARGET-30-PAUDDZ-01A-01D, TARGET-30-PARHDE-01A-01D, TARGET-30-PATBAC-01A-01D, TARGET-30-PASALE-01A-01D, TARGET-30-PASPGU-01A-01D, TARGET-30-PASWVE-01A-01D, TARGET-30-PAICGF-01A-01W, TARGET-10-PANTLF-03A-01D, TARGET-30-PAMCXF-01A-01W, TARGET-30-PATCDJ-01A-01D, TARGET-30-PASGCD-01A-01D, TARGET-30-PASKZT-01A-01D, TARGET-30-PATYMZ-01A-01D, TARGET-30-PASZYY-01A-01D, TARGET-30-PAIXNC-01A-01W, TARGET-30-PASBDN-01A-01D, TARGET-20-PANSBH-04A-01D, TARGET-10-PARLMI-09A-01D, TARGET-30-PAKIPY-01A-01W, TARGET-30-PAUBDC-01A-01D, TARGET-30-PAUZSB-01A-01D, TARGET-30-PAUYXX-01A-01D, TARGET-30-PAUKNU-01A-01D, TARGET-30-PASJTA-01A-01D, TARGET-10-PARKFN-09A-01D, TARGET-30-PAUNWR-01A-01D, TARGET-30-PAUGZD-01A-01D, TARGET-30-PALETP-01A-01W, TARGET-30-PAUDPP-01A-01D, TARGET-30-PAUJLH-01A-01D, TARGET-30-PASYTP-01A-01D, TARGET-30-PATAFE-01A-01D, TARGET-30-PAUMBB-01A-01D, TARGET-10-PARATY-09A-01D, TARGET-30-PASKKZ-01A-01D, TARGET-10-PANVIC-03A-01D, TARGET-30-PAKHCF-01A-01W, TARGET-30-PAUYDE-01A-01D, TARGET-30-PASAJY-01A-01D, TARGET-30-PASJWG-01A-01D, TARGET-30-PASAAN-01A-01D, TARGET-30-PATLCM-01A-01D, TARGET-30-PATXXI-01A-01D, TARGET-30-PATVWA-01A-01D, TARGET-30-PASJWA-01A-01D, TARGET-10-PAPADT-09A-01D, TARGET-30-PASMET-01A-01D, TARGET-30-PAUHYY-01A-01D, TARGET-30-PARYVD-01A-01D, TARGET-30-PAUBSW-01A-01D, TARGET-30-PASLPG-01A-01D, TARGET-30-PAUGRP-01A-01D, TARGET-30-PASCZY-01A-01D, TARGET-10-PAPHBW-09A-01D, TARGET-10-PAPAGS-09A-01D, TARGET-30-PATNRI-01A-01D, TARGET-30-PASCEW-09A-01D, TARGET-30-PARUGX-01A-01D, TARGET-30-PAPEFE-01A-01W, TARGET-30-PATUEH-01A-01D, TARGET-30-PAIXNV-01A-01W, TARGET-30-PAULVH-01A-01D, TARGET-30-PATXUG-01A-01D, TARGET-10-PANSYA-09A-01D, TARGET-30-PASLMN-01A-01D, TARGET-30-PAVCKK-01A-01D, TARGET-30-PAKVUY-01A-01D, TARGET-10-PARCKV-09A-01D, TARGET-10-PAPGEE-09A-01D, TARGET-10-PARCTN-09A-01D, TARGET-30-PATTFB-01A-01D, TARGET-30-PATBKX-01A-01D, TARGET-10-PAPIHU-09A-01D, TARGET-30-PATIYD-09A-01D, TARGET-30-PASZJB-01A-01D, TARGET-30-PATXKG-01A-01D, TARGET-30-PATFTN-01A-01D, TARGET-10-PAPDDA-09A-01D, TARGET-10-PAPCNP-09A-01D, TARGET-30-PASLTC-01A-01D, TARGET-30-PATLUI-01A-01D, TARGET-30-PARVVM-09A-01D, TARGET-30-PASVWG-01A-01D, TARGET-30-PASTIJ-01A-01D, TARGET-30-PASFKX-01A-01D, TARGET-10-PARDKG-09A-01D, TARGET-30-PATBPG-01A-01D, TARGET-30-PASSEC-01A-01D, TARGET-30-PAUXFZ-01A-01D, TARGET-30-PATDFU-01A-01D, TARGET-10-PARBRX-09A-01D, TARGET-30-PALJUV-01A-01W, TARGET-30-PATSDR-01A-01D, TARGET-10-PARMMA-09A-01D, TARGET-10-PARCMG-03A-01D, TARGET-10-PAPCVI-09A-01D, TARGET-30-PASEGF-01A-01D, TARGET-30-PAUBRR-01A-01D, TARGET-10-PAPAGK-03A-01D, TARGET-30-PATZIG-01A-01D, TARGET-10-PAPIJD-09A-01D, TARGET-50-PAJLWT-01A-01D, TARGET-50-PAJLNJ-01A-01D, TARGET-50-PAJNLT-01A-01D, TARGET-10-PASMIC-09A-01D, TARGET-10-PARAYM-09A-01D, TARGET-10-PATDBU-09A-01D, TARGET-10-PASMNV-09A-01D, TARGET-10-PATNIA-09A-01D, TARGET-50-PAJPAR-01A-01D, TARGET-40-PARFTG-01A-01D, TARGET-10-PASZEW-09A-01D, TARGET-30-PASXRJ-01A-01D, TARGET-30-PASKYH-01A-01D, TARGET-10-PAPHLH-09A-01D, TARGET-30-PATSRD-01A-01D, TARGET-30-PASPXU-01A-01D, TARGET-30-PAIXRK-01A-01W, TARGET-30-PATJXV-01A-01D, TARGET-30-PATBRX-01A-01D, TARGET-10-PAPERN-09A-01D, TARGET-30-PAUMMZ-01A-01D, TARGET-30-PASCFA-01A-01D, TARGET-10-PARBIX-03A-01D, TARGET-30-PARXMM-01A-01D, TARGET-30-PATMXC-01A-01D, TARGET-30-PATWGC-01A-01D, TARGET-30-PASLIH-01A-01D, TARGET-30-PAUWYM-01A-01D, TARGET-30-PAKGKH-01A-01W, TARGET-30-PAUICI-01A-01D, TARGET-30-PATPPK-01A-01D, TARGET-30-PANKFE-01A-01W, TARGET-30-PASFGD-01A-01D, TARGET-30-PAURCG-01A-01D, TARGET-30-PAUZMG-01A-01D, TARGET-30-PARXVA-01A-01D, TARGET-30-PARUPT-01A-01D, TARGET-30-PARXMH-01A-01D, TARGET-30-PASFNF-01A-01D, TARGET-30-PARYWX-01A-01D, TARGET-30-PASFDV-01A-01D, TARGET-30-PALZZV-01A-01W, TARGET-30-PAUBYW-01A-01D, TARGET-30-PASEAR-01A-01D, TARGET-30-PATUNZ-01A

Add total mutations per sample.

# Count the total number of signature mutations for each sample
total_muts <- apply(sigs_input, 1, sum)

Determine Signatures for COSMIC and Alexandrov et al, 2013

Get list of tumor sample ids.

tumor_sample_ids <- maf %>%
  dplyr::filter(Tumor_Sample_Barcode %in% rownames(sigs_input)) %>%
  dplyr::distinct(Tumor_Sample_Barcode) %>%
  dplyr::pull(Tumor_Sample_Barcode)

Get COSMIC v2 signatures for each sample. This step will take some time.

sample_sigs_cosmic <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic,
    sample.id = sample_id,
    contexts.needed = TRUE
  )
})
# Bring along the names
names(sample_sigs_cosmic) <- tumor_sample_ids

# Create matrix of COSMIC signature weights
cosmic_weights <- lapply(sample_sigs_cosmic, "[[", "weights")
cosmic_wide <- do.call(dplyr::bind_rows, cosmic_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(cosmic_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
readr::write_tsv(file.path(results_dir, 'cosmicv2_signature_exposure_matrix.tsv'))

Get Alexandrov et al, 2013 signatures for each sample.

sample_sigs_nature <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.nature2013,
    sample.id = sample_id,
    contexts.needed = TRUE
  )
})
# Bring along the names
names(sample_sigs_nature) <- tumor_sample_ids

# Create data frame of Nature signature weights
nature_weights <- lapply(sample_sigs_nature, "[[", "weights")
nature_wide <- do.call(dplyr::bind_rows, nature_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(nature_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
readr::write_tsv(file.path(results_dir, 'nature_signature_exposure_matrix.tsv'))

Get COSMIC genome v3.3 signatures for each sample.

signatures.cosmic.v3.3 <- read_tsv(file.path(input_dir, 'COSMIC_v3.3.1_SBS_GRCh38.txt')) %>%
  column_to_rownames('Type') %>%
  t %>%
  as.data.frame()
Rows: 96 Columns: 80
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr  (1): Type
dbl (79): SBS1, SBS2, SBS3, SBS4, SBS5, SBS6, SBS7a, SBS7b, SBS7c, SBS7d, SB...

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.

Create list of include/exclude signatures using SBSv3 mapping file. For Initial CNS tumors, therapy exposures will be excluded, but they will be retained for other tumor types.

map <- read_tsv(file.path(input_dir, "sbs_v3_map.tsv"))
Rows: 79 Columns: 4
── Column specification ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Delimiter: "\t"
chr (4): Signature, Meaning, Broad_category, Narrow_category

ℹ Use `spec()` to retrieve the full column specification for this data.
ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.
# Excluded signatures:
artifact_sigs <- map %>%
   filter(Broad_category == "Sequencing artifact") %>%
   pull(Signature)

environ_sigs <- map %>%
   filter(Broad_category == "Environmental exposure") %>%
   pull(Signature)

unknown <- map %>%
   filter(Broad_category == "Unknown" & Signature != "SBS39") %>%
   pull(Signature)
 
therapy_sigs <- map %>%
   filter(Broad_category == "Therapy exposure") %>%
   pull(Signature)

exclude_sigs <- c(artifact_sigs, environ_sigs, unknown)
include_sigs_initialPretx <- setdiff(rownames(signatures.cosmic.v3.3), c(exclude_sigs, therapy_sigs))
include_sigs_other <- setdiff(rownames(signatures.cosmic.v3.3), exclude_sigs)

Run signature extraction. This step will take some time.

sample_sigs_cosmic_v33 <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  if (sample_id %in% initial_pretx_tumors){
    whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic.v3.3,
    sample.id = sample_id,
    contexts.needed = TRUE,
    associated = include_sigs_initialPretx
    )
  }else{
    whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic.v3.3,
    sample.id = sample_id,
    contexts.needed = TRUE,
    associated = include_sigs_other
    )
  }
})

# Bring along the names
names(sample_sigs_cosmic_v33) <- tumor_sample_ids
# 
# Create matrix of COSMIC signature weights
cosmic_v33_weights <- lapply(sample_sigs_cosmic_v33, "[[", "weights")
cosmic_v33_wide <- do.call(dplyr::bind_rows, cosmic_v33_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(cosmic_v33_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
  readr::write_tsv(file.path(results_dir, 'cosmicv3.3_signature_exposure_matrix.tsv'))

Calculate the mutations per Mb for each signature

Do this for COSMIC v2 mutation signatures.

# Calculate mutations per signature
cosmic_sigs_df <- calc_mut_per_sig(
  sample_sigs_cosmic,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
)  %>%
  dplyr::filter(grepl("Signature", signature))
Using Tumor_Sample_Barcode, sample_id, aliquot_id, Kids_First_Participant_ID, experimental_strategy, sample_type, composition, tumor_descriptor, primary_site, reported_gender, race, ethnicity, pathology_diagnosis, RNA_library, OS_status, cohort, seq_center, cancer_predispositions, pathology_free_text_diagnosis, cohort_participant_id, extent_of_tumor_resection, CNS_region, gtex_group, gtex_subgroup, germline_sex_estimate, clinical_status_at_event, cell_line_composition, dkfz_v11_methylation_subclass, dkfz_v12_methylation_subclass, dkfz_v12_methylation_mgmt_status, molecular_subtype, integrated_diagnosis, Notes, harmonized_diagnosis, molecular_subtype_methyl, broad_histology, short_histology, cancer_group, display_group, hex_codes as id variables
Warning: attributes are not identical across measure variables; they will be
dropped
# Write this to a file but drop the color column
cosmic_sigs_df %>% 
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "cosmicv2_signatures_results.tsv"))

# Print out a preview
cosmic_sigs_df

Do this for COSMIC v3.3 mutation signatures.

# Calculate mutations per signature
cosmicv3_sigs_df <- calc_mut_per_sig(
  sample_sigs_cosmic_v33,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
) %>%
  dplyr::filter(grepl("SBS", signature))
Using Tumor_Sample_Barcode, sample_id, aliquot_id, Kids_First_Participant_ID, experimental_strategy, sample_type, composition, tumor_descriptor, primary_site, reported_gender, race, ethnicity, pathology_diagnosis, RNA_library, OS_status, cohort, seq_center, cancer_predispositions, pathology_free_text_diagnosis, cohort_participant_id, extent_of_tumor_resection, CNS_region, gtex_group, gtex_subgroup, germline_sex_estimate, clinical_status_at_event, cell_line_composition, dkfz_v11_methylation_subclass, dkfz_v12_methylation_subclass, dkfz_v12_methylation_mgmt_status, molecular_subtype, integrated_diagnosis, Notes, harmonized_diagnosis, molecular_subtype_methyl, broad_histology, short_histology, cancer_group, display_group, hex_codes as id variables
Warning: attributes are not identical across measure variables; they will be
dropped
# Write this to a file but drop the color column
cosmicv3_sigs_df %>% 
#  dplyr::filter(grepl("SBS", signature)) %>%
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "cosmicv3.3_signatures_results.tsv"))

# Print out a preview
cosmicv3_sigs_df

Do this for Alexandrov et al, 2013 mutation signatures.

#Calculate mutations per signature
nature_sigs_df <- calc_mut_per_sig(
  sample_sigs_nature,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
)  %>%
  dplyr::filter(grepl("Signature", signature))
Using Tumor_Sample_Barcode, sample_id, aliquot_id, Kids_First_Participant_ID, experimental_strategy, sample_type, composition, tumor_descriptor, primary_site, reported_gender, race, ethnicity, pathology_diagnosis, RNA_library, OS_status, cohort, seq_center, cancer_predispositions, pathology_free_text_diagnosis, cohort_participant_id, extent_of_tumor_resection, CNS_region, gtex_group, gtex_subgroup, germline_sex_estimate, clinical_status_at_event, cell_line_composition, dkfz_v11_methylation_subclass, dkfz_v12_methylation_subclass, dkfz_v12_methylation_mgmt_status, molecular_subtype, integrated_diagnosis, Notes, harmonized_diagnosis, molecular_subtype_methyl, broad_histology, short_histology, cancer_group, display_group, hex_codes as id variables
Warning: attributes are not identical across measure variables; they will be
dropped
# Write this to a file but drop the color column
nature_sigs_df %>% 
#  dplyr::filter(grepl("SBS", signature)) %>%
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "nature_signatures_results.tsv"))

# Print out a preview
nature_sigs_df

Mutation signature bubble matrix by histology groups

For COSMIC v2 signatures

bubble_matrix_plot(cosmic_sigs_df, 
                   label = "COSMIC Signatures", 
                   color_palette = gradient_col_palette$hex_codes
)
`summarise()` has grouped output by 'display_group'. You can override using the
`.groups` argument.
Warning: Removed 207 rows containing missing values (`geom_point()`).

ggplot2::ggsave(
  file.path(cosmicv2_plots, "bubble_matrix_cosmicv2_mutation_sig.png"),
  width = 30, height = 20, units = "cm")
Warning: Removed 207 rows containing missing values (`geom_point()`).

For Nature signatures

bubble_matrix_plot(nature_sigs_df, 
                   label = "Alexandrov et al, 2013 signatures", 
                   color_palette = gradient_col_palette$hex_codes)
`summarise()` has grouped output by 'display_group'. You can override using the
`.groups` argument.
Warning: Removed 151 rows containing missing values (`geom_point()`).

ggplot2::ggsave(
  file.path(nature_plots, "bubble_matrix_nature_mutation_sig.png"), 
  width = 30, height = 20, units = "cm")
Warning: Removed 151 rows containing missing values (`geom_point()`).

For COSMIC v3.3 signatures

bubble_matrix_plot(cosmicv3_sigs_df, 
                   label = "COSMIC Signatures", 
                   color_palette = gradient_col_palette$hex_codes
)
`summarise()` has grouped output by 'display_group'. You can override using the
`.groups` argument.
Warning: Removed 986 rows containing missing values (`geom_point()`).

ggplot2::ggsave(
  file.path(cosmicv3_plots, "bubble_matrix_cosmicv3_mutation_sig.png"),
  width = 30, height = 20, units = "cm")
Warning: Removed 986 rows containing missing values (`geom_point()`).

Mutation signature grouped bar plots for each histology group

We will make these plots for primary tumor samples only. Lets make these for COSMIC mutation signatures first.

# Make grouped bar plots
lapply(unique(cosmic_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = cosmic_sigs_df,
  output_dir = file.path(cosmicv2_scratch, "signature_grouped_barplots"), 
  label = "cosmic_v2"
)
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Make these plots for Alexandrov et al, 2013 signatures.

# Make grouped bar plots
lapply(unique(nature_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = nature_sigs_df,
  output_dir = file.path(nature_scratch, "signature_grouped_barplots"),
  label = "nature"
)
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Make these plots for COSMIC v3.3 signatures.

# Make grouped bar plots
lapply(unique(cosmicv3_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = cosmicv3_sigs_df,
  output_dir = file.path(cosmicv3_scratch, "signature_grouped_barplots"),
  label = "cosmic_v3.3"
)
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Session Info

sessionInfo()
R version 4.2.3 (2023-03-15)
Platform: x86_64-pc-linux-gnu (64-bit)
Running under: Ubuntu 22.04.2 LTS

Matrix products: default
BLAS:   /usr/lib/x86_64-linux-gnu/openblas-pthread/libblas.so.3
LAPACK: /usr/lib/x86_64-linux-gnu/openblas-pthread/libopenblasp-r0.3.20.so

locale:
 [1] LC_CTYPE=en_US.UTF-8       LC_NUMERIC=C              
 [3] LC_TIME=en_US.UTF-8        LC_COLLATE=en_US.UTF-8    
 [5] LC_MONETARY=en_US.UTF-8    LC_MESSAGES=en_US.UTF-8   
 [7] LC_PAPER=en_US.UTF-8       LC_NAME=C                 
 [9] LC_ADDRESS=C               LC_TELEPHONE=C            
[11] LC_MEASUREMENT=en_US.UTF-8 LC_IDENTIFICATION=C       

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
 [1] lubridate_1.9.2       forcats_1.0.0         stringr_1.5.0        
 [4] dplyr_1.1.1           purrr_1.0.1           readr_2.1.4          
 [7] tidyr_1.3.0           tibble_3.2.1          ggplot2_3.4.2        
[10] tidyverse_2.0.0       deconstructSigs_1.9.0

loaded via a namespace (and not attached):
 [1] Biobase_2.58.0                    MatrixGenerics_1.10.0            
 [3] sass_0.4.5                        bit64_4.0.5                      
 [5] vroom_1.6.1                       jsonlite_1.8.4                   
 [7] R.utils_2.12.2                    bslib_0.4.2                      
 [9] highr_0.10                        stats4_4.2.3                     
[11] BSgenome_1.66.3                   GenomeInfoDbData_1.2.9           
[13] Rsamtools_2.14.0                  yaml_2.3.7                       
[15] lattice_0.21-8                    pillar_1.9.0                     
[17] glue_1.6.2                        digest_0.6.31                    
[19] GenomicRanges_1.50.2              XVector_0.38.0                   
[21] colorspace_2.1-0                  plyr_1.8.8                       
[23] Matrix_1.5-4                      htmltools_0.5.5                  
[25] R.oo_1.25.0                       XML_3.99-0.14                    
[27] pkgconfig_2.0.3                   zlibbioc_1.44.0                  
[29] scales_1.2.1                      tzdb_0.3.0                       
[31] BiocParallel_1.32.6               timechange_0.2.0                 
[33] generics_0.1.3                    farver_2.1.1                     
[35] IRanges_2.32.0                    SummarizedExperiment_1.28.0      
[37] cachem_1.0.7                      withr_2.5.0                      
[39] BiocGenerics_0.44.0               cli_3.6.1                        
[41] magrittr_2.0.3                    crayon_1.5.2                     
[43] evaluate_0.20                     R.methodsS3_1.8.2                
[45] fansi_1.0.4                       textshaping_0.3.6                
[47] tools_4.2.3                       data.table_1.14.8                
[49] hms_1.1.3                         BiocIO_1.8.0                     
[51] lifecycle_1.0.3                   matrixStats_0.63.0               
[53] S4Vectors_0.36.2                  munsell_0.5.0                    
[55] DelayedArray_0.24.0               Biostrings_2.66.0                
[57] compiler_4.2.3                    jquerylib_0.1.4                  
[59] GenomeInfoDb_1.34.9               systemfonts_1.0.4                
[61] rlang_1.1.0                       grid_4.2.3                       
[63] RCurl_1.98-1.12                   rjson_0.2.21                     
[65] bitops_1.0-7                      labeling_0.4.2                   
[67] rmarkdown_2.21                    restfulr_0.0.15                  
[69] gtable_0.3.3                      codetools_0.2-19                 
[71] reshape2_1.4.4                    R6_2.5.1                         
[73] GenomicAlignments_1.34.1          knitr_1.42                       
[75] rtracklayer_1.58.0                fastmap_1.1.1                    
[77] bit_4.0.5                         utf8_1.2.3                       
[79] ragg_1.2.5                        stringi_1.7.12                   
[81] Rcpp_1.0.10                       parallel_4.2.3                   
[83] vctrs_0.6.2                       tidyselect_1.2.0                 
[85] xfun_0.38                         BSgenome.Hsapiens.UCSC.hg38_1.4.5
---
title: "SBS Mutational Signatures Analysis"
output: 
  html_notebook:
  toc: TRUE
toc_float: TRUE
author: Ryan Corbett (adapted from C. Savonen for ALSF CCDL)
date: 2022
---
  
  **Purpose:**
  
Calculate and plot mutational signatures for all samples using [COSMIC signatures](https://cancer.sanger.ac.uk/cosmic) and 
[Alexandrov et al, 2013](https://www.ncbi.nlm.nih.gov/pubmed/23945592) mutational signatures. 

#### Usage

To run this from the command line, use:
  ```
Rscript -e "rmarkdown::render('analyses/mutational-signatures/01-known_signatures.Rmd', 
                              clean = TRUE)"
```

_This assumes you are in the top directory of the repository._

## Setup

#### Packages and functions

Import necessary functions.

```{r load libraries}
# Magrittr pipe
`%>%` <- dplyr::`%>%`

# Import specialized functions
source(file.path("util", "mut_sig_functions.R"))

# Load this library
library(deconstructSigs)
library(tidyverse)
```

Set up directory paths. 

```{r set directories}
data_dir <- file.path("..", "..", "data")
input_dir <- "input"
results_dir <- "results"
plots_dir <- "plots"
figures_dir <- file.path("..", "..", "figures")

cosmicv2_plots <- file.path(plots_dir, "cosmicv2")
nature_plots <- file.path(plots_dir, "nature")
cosmicv3_plots <- file.path(plots_dir, "cosmicv3")

scratch_dir <- file.path("..", "..", "scratch", "mutational-signatures")
cosmicv2_scratch <- file.path(scratch_dir, "cosmicv2")
cosmicv3_scratch <- file.path(scratch_dir, "cosmicv3")
nature_scratch <- file.path(scratch_dir, "nature")
```

Make new directories for the results. 

```{r make directories}
if (!dir.exists(results_dir)) {
  dir.create(results_dir)
}
if (!dir.exists(cosmicv2_plots)) {
  dir.create(cosmicv2_plots, recursive = TRUE)
}
if (!dir.exists(nature_plots)) {
  dir.create(nature_plots, recursive = TRUE)
}
if (!dir.exists(cosmicv3_plots)) {
  dir.create(cosmicv3_plots, recursive = TRUE)
}

if (!dir.exists(scratch_dir)) {
  dir.create(scratch_dir)
}
if (!dir.exists(cosmicv2_scratch)) {
  dir.create(cosmicv2_scratch)
}
if (!dir.exists(cosmicv3_scratch)) {
  dir.create(cosmicv3_scratch)
}
if (!dir.exists(nature_scratch)) {
  dir.create(nature_scratch)
}
```

## Read in data

```{r}
# Declare file path for consensus file
consensus_file <- file.path(data_dir, "snv-consensus-plus-hotspots.maf.tsv.gz")
```

Read in the consensus MAF file. 

```{r}
# Read in the file
maf <- data.table::fread(consensus_file, data.table = FALSE)
```

### Read in color palettes

Read in the histology colors and labels. 

```{r}
histology_label_mapping <- readr::read_tsv(
  file.path(figures_dir, "palettes", "histology_label_color_table.tsv")
) %>% 
  # Select just the columns we will need for plotting
  dplyr::select(Kids_First_Biospecimen_ID, display_group, display_order, hex_codes) %>% 
  # Reorder display_group based on display_order
  dplyr::mutate(display_group = forcats::fct_reorder(display_group, display_order))
```

Set up gradient color palette for the bubble matrix plots. 

```{r}
gradient_col_palette <- readr::read_tsv(
  file.path(figures_dir, "palettes", "gradient_color_palette.tsv")
)

# Won't need NA color this time. 
gradient_col_palette <- gradient_col_palette %>%
  dplyr::filter(color_names != "na_color")
```

Read in the metadata and set it up with the color palette. Separate BS_ids into intial CNS tumors and other tumors, as mutational signatures analyses will be run on a different set of signatures for each group.  

```{r}
metadata_df <- readr::read_tsv(file.path(data_dir, "histologies.tsv"), guess_max = 10000) %>% 
#  dplyr::select("Kids_First_Biospecimen_ID", "experimental_strategy") %>%
  dplyr::inner_join(histology_label_mapping, by = "Kids_First_Biospecimen_ID") %>% 
  dplyr::rename(Tumor_Sample_Barcode = "Kids_First_Biospecimen_ID") 

initial_pretx_tumors <- metadata_df %>%
  filter(tumor_descriptor == "Initial CNS Tumor" & age_at_diagnosis_days < age_at_chemo_start) %>%
  pull(Tumor_Sample_Barcode)
  

# pretx_tumors <- readr::read_tsv(file.path(input_dir, "CBTN_all_therapy_20220922.tsv")) %>%
#   mutate(Pretreatment = case_when(`Age at Diagnosis` < `Age at Chemotherapy Start` ~ "yes",
#                                   `Age at Diagnosis` > `Age at Chemotherapy Start` ~ "no",
#                                   TRUE ~ as.character(NA))) %>%
#   filter(Pretreatment == "yes") %>%
#   pull(cohort_participant_id)
# 
# initial_pretx_tumors <- metadata_df %>%
#   filter(tumor_descriptor == "Initial CNS Tumor" & cohort_participant_id %in% pretx_tumors) %>%
#   pull(Tumor_Sample_Barcode)
```

Read in tmb-all file with WGS and WXS region lengths so they can be used for the Mb denominator. 

```{r}
# Set up BED region file for TMB calculations
region_sizes <- readr::read_tsv(file.path(data_dir, "snv-mutation-tmb-all.tsv")) %>%
  dplyr::select(Tumor_Sample_Barcode, region_size)
```

## Set up data

Determine how many mutations we have per sample.

```{r}
mut_per_sample <- maf %>%
  dplyr::group_by(Tumor_Sample_Barcode) %>%
  dplyr::tally() %>%
  dplyr::arrange(n)

summary(mut_per_sample$n)
```

Graph this.

```{r}
ggplot2::ggplot(mut_per_sample, ggplot2::aes(x = n, geom = "density")) +
  ggplot2::geom_density() +
  ggplot2::theme_classic()
```

Make mutation data into `deconstructSigs` input format.

```{r}
# Convert to deconstructSigs input
sigs_input <- mut.to.sigs.input(
  mut.ref = maf,
  sample.id = "Tumor_Sample_Barcode",
  chr = "Chromosome",
  pos = "Start_Position",
  ref = "Reference_Allele",
  alt = "Allele",
  bsg = BSgenome.Hsapiens.UCSC.hg38::BSgenome.Hsapiens.UCSC.hg38
)
```

Add total mutations per sample. 

```{r}
# Count the total number of signature mutations for each sample
total_muts <- apply(sigs_input, 1, sum)
```

## Determine Signatures for COSMIC and Alexandrov et al, 2013

Get list of tumor sample ids. 

```{r}
tumor_sample_ids <- maf %>%
  dplyr::filter(Tumor_Sample_Barcode %in% rownames(sigs_input)) %>%
  dplyr::distinct(Tumor_Sample_Barcode) %>%
  dplyr::pull(Tumor_Sample_Barcode)
```

Get [COSMIC v2 signatures](https://cancer.sanger.ac.uk/cosmic) for each sample. 
This step will take some time. 

```{r}
sample_sigs_cosmic <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic,
    sample.id = sample_id,
    contexts.needed = TRUE
  )
})
# Bring along the names
names(sample_sigs_cosmic) <- tumor_sample_ids

# Create matrix of COSMIC signature weights
cosmic_weights <- lapply(sample_sigs_cosmic, "[[", "weights")
cosmic_wide <- do.call(dplyr::bind_rows, cosmic_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(cosmic_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
readr::write_tsv(file.path(results_dir, 'cosmicv2_signature_exposure_matrix.tsv'))
```

Get [Alexandrov et al, 2013](https://www.ncbi.nlm.nih.gov/pubmed/23945592) signatures for each sample. 

```{r}
sample_sigs_nature <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.nature2013,
    sample.id = sample_id,
    contexts.needed = TRUE
  )
})
# Bring along the names
names(sample_sigs_nature) <- tumor_sample_ids

# Create data frame of Nature signature weights
nature_weights <- lapply(sample_sigs_nature, "[[", "weights")
nature_wide <- do.call(dplyr::bind_rows, nature_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(nature_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
readr::write_tsv(file.path(results_dir, 'nature_signature_exposure_matrix.tsv'))
```

Get [COSMIC genome v3.3 signatures](https://cancer.sanger.ac.uk/cosmic) for each sample. 

```{r}
signatures.cosmic.v3.3 <- read_tsv(file.path(input_dir, 'COSMIC_v3.3.1_SBS_GRCh38.txt')) %>%
  column_to_rownames('Type') %>%
  t %>%
  as.data.frame()
```

Create list of include/exclude signatures using SBSv3 mapping file. For Initial CNS tumors, therapy exposures will be excluded, but they will be retained for other tumor types. 

```{r Set up lists of excluded and included signatures for COSMIC V3}
map <- read_tsv(file.path(input_dir, "sbs_v3_map.tsv"))

# Excluded signatures:
artifact_sigs <- map %>%
   filter(Broad_category == "Sequencing artifact") %>%
   pull(Signature)

environ_sigs <- map %>%
   filter(Broad_category == "Environmental exposure") %>%
   pull(Signature)

unknown <- map %>%
   filter(Broad_category == "Unknown" & Signature != "SBS39") %>%
   pull(Signature)
 
therapy_sigs <- map %>%
   filter(Broad_category == "Therapy exposure") %>%
   pull(Signature)

exclude_sigs <- c(artifact_sigs, environ_sigs, unknown)
include_sigs_initialPretx <- setdiff(rownames(signatures.cosmic.v3.3), c(exclude_sigs, therapy_sigs))
include_sigs_other <- setdiff(rownames(signatures.cosmic.v3.3), exclude_sigs)
```

Run signature extraction. This step will take some time.

```{r}
sample_sigs_cosmic_v33 <- lapply(tumor_sample_ids, function(sample_id) {
  # Determine the signatures contributing to the sample
  if (sample_id %in% initial_pretx_tumors){
    whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic.v3.3,
    sample.id = sample_id,
    contexts.needed = TRUE,
    associated = include_sigs_initialPretx
    )
  }else{
    whichSignatures(
    tumor.ref = sigs_input,
    signatures.ref = signatures.cosmic.v3.3,
    sample.id = sample_id,
    contexts.needed = TRUE,
    associated = include_sigs_other
    )
  }
})

# Bring along the names
names(sample_sigs_cosmic_v33) <- tumor_sample_ids
# 
# Create matrix of COSMIC signature weights
cosmic_v33_weights <- lapply(sample_sigs_cosmic_v33, "[[", "weights")
cosmic_v33_wide <- do.call(dplyr::bind_rows, cosmic_v33_weights) %>%
  add_column('Kids_First_Biospecimen_ID' = unlist(lapply(cosmic_v33_weights, rownames)), .before = 1) %>%
  tibble::as_tibble() %>%
  readr::write_tsv(file.path(results_dir, 'cosmicv3.3_signature_exposure_matrix.tsv'))
```

### Calculate the mutations per Mb for each signature

Do this for COSMIC v2 mutation signatures.

```{r}
# Calculate mutations per signature
cosmic_sigs_df <- calc_mut_per_sig(
  sample_sigs_cosmic,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
)  %>%
  dplyr::filter(grepl("Signature", signature))

# Write this to a file but drop the color column
cosmic_sigs_df %>% 
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "cosmicv2_signatures_results.tsv"))

# Print out a preview
cosmic_sigs_df
```

Do this for COSMIC v3.3 mutation signatures.

```{r}
# Calculate mutations per signature
cosmicv3_sigs_df <- calc_mut_per_sig(
  sample_sigs_cosmic_v33,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
) %>%
  dplyr::filter(grepl("SBS", signature))

# Write this to a file but drop the color column
cosmicv3_sigs_df %>% 
#  dplyr::filter(grepl("SBS", signature)) %>%
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "cosmicv3.3_signatures_results.tsv"))

# Print out a preview
cosmicv3_sigs_df
```

Do this for Alexandrov et al, 2013 mutation signatures.

```{r}
#Calculate mutations per signature
nature_sigs_df <- calc_mut_per_sig(
  sample_sigs_nature,
  muts_per_sample = total_muts,
  region_size = region_sizes,
  metadata = metadata_df
)  %>%
  dplyr::filter(grepl("Signature", signature))

# Write this to a file but drop the color column
nature_sigs_df %>% 
#  dplyr::filter(grepl("SBS", signature)) %>%
  dplyr::select(-hex_codes) %>% 
  readr::write_tsv(file.path(results_dir, "nature_signatures_results.tsv"))

# Print out a preview
nature_sigs_df
```

## Mutation signature bubble matrix by histology groups

For COSMIC v2 signatures

```{r}
bubble_matrix_plot(cosmic_sigs_df, 
                   label = "COSMIC Signatures", 
                   color_palette = gradient_col_palette$hex_codes
)
```

```{r}
ggplot2::ggsave(
  file.path(cosmicv2_plots, "bubble_matrix_cosmicv2_mutation_sig.png"),
  width = 30, height = 20, units = "cm")
```


For Nature signatures

```{r}
bubble_matrix_plot(nature_sigs_df, 
                   label = "Alexandrov et al, 2013 signatures", 
                   color_palette = gradient_col_palette$hex_codes)
```

```{r}
ggplot2::ggsave(
  file.path(nature_plots, "bubble_matrix_nature_mutation_sig.png"), 
  width = 30, height = 20, units = "cm")
```


For COSMIC v3.3 signatures

```{r}
bubble_matrix_plot(cosmicv3_sigs_df, 
                   label = "COSMIC Signatures", 
                   color_palette = gradient_col_palette$hex_codes
)
```

```{r}
ggplot2::ggsave(
  file.path(cosmicv3_plots, "bubble_matrix_cosmicv3_mutation_sig.png"),
  width = 30, height = 20, units = "cm")
```

## Mutation signature grouped bar plots for each histology group

We will make these plots for primary tumor samples only. 
Lets make these for COSMIC mutation signatures first. 

```{r, results = "hide"}
# Make grouped bar plots
lapply(unique(cosmic_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = cosmic_sigs_df,
  output_dir = file.path(cosmicv2_scratch, "signature_grouped_barplots"), 
  label = "cosmic_v2"
)
```

Make these plots for Alexandrov et al, 2013 signatures. 

```{r, results = "hide"}
# Make grouped bar plots
lapply(unique(nature_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = nature_sigs_df,
  output_dir = file.path(nature_scratch, "signature_grouped_barplots"),
  label = "nature"
)
```

Make these plots for COSMIC v3.3 signatures. 

```{r, results = "hide"}
# Make grouped bar plots
lapply(unique(cosmicv3_sigs_df$display_group),
  grouped_sig_barplot,
  sig_num_df = cosmicv3_sigs_df,
  output_dir = file.path(cosmicv3_scratch, "signature_grouped_barplots"),
  label = "cosmic_v3.3"
)
```



## Session Info

```{r}
sessionInfo()
```
